Synthesis and antioxidant activity of DOPA peptidomimetics by a novel IBX mediated aromatic oxidative functionalization

Abstract

DOPA peptidomimetics with stable O-C and N-C covalent bonds between amino acid residues have been prepared by aromatic oxidative functionalization of tyrosine with 2-iodoxybenzoic acid (IBX). The reaction involves the Michael-like nucleophilic addition of different oxygen and nitrogen protected amino acids on a reactive DOPA quinone intermediate. Similar results were obtained in heterogeneous conditions using supported IBX-amide for more runs. Among the novel derivatives, compounds containing glycine residues showed a more pronounced antioxidant activity in the 2,2-diphenyl picrylhydrazyl (DPPH) radical scavenging cell free assay. Instead, valine derivatives showed the highest biological effect in L5178Y mouse lymphoma cells, by assessing the ability to reduce H 2 O 2 induced DNA breakage in the alkaline comet assay. a Reaction conditions: compound 1 (0.1 mmol) was dissolved in THF (1.5 mL) in the presence of the appropriate protected a-amino acids 2-9 (1.0 mmol) and treated with IBX (0.3 mmol) at 45 C for 72 h. b Reaction performed at 25 C for 3 h. This journal is View Article Online a Reaction conditions: compound 1 (0.1 mmol) was dissolved in the appropriate solvent (1.5 mL) in the presence of protected a-amino acids 19-26 (1.0 mmol) and treated with IBX (0.3 mmol) at 45 C for 72 h. 60356 | RSC Adv., 2015, 5, 60354-60364 This journal is

Tyrosinase mediated oxidative functionalization in the synthesis of DOPA-derived peptidomimetics with anti-Parkinson activity

“…Preliminary studies showed that DOPA-derived peptidomimetics 2-5 were characterized by an antioxidant activity higher than that of the corresponding DOPA-containing peptides. 20 On the basis of these data, we decided to evaluate the anti-PD effect of peptidomimetics 2-9 (protected and deprotected forms) on DAergic neurons. Since PD is characterized by low content of DA in the basal ganglia nuclei, potential anti-PD drugs should mimic the effects of DA and/or DOPA.…”

“…[15][16][17][18] The replacement of the natural amide bond in peptides with unusual covalent linkages is a general strategy to improve the stability and activity of the molecule. 19 We recently reported the synthesis of DOPA-derived peptidomimetics with stable O-C and N-C covalent bonds by oxidative functionalization of tyrosine with 2-iodoxybenzoic acid (IBX), 20 that is a biomimetic system of tyrosinase. The reaction proceeded through a Michael-like 1,4-addition of oxygen and nitrogen centred aamino acids to reactive DOPA ortho-quinone intermediate.…”

“…21 DOPA-derived peptidomimetics containing glycine residues showed the highest antioxidant effect in the 2,2-diphenyl picrylhydrazyl (DPPH) test, while valine derivatives were the most active compounds in the comet assay in L5178Y (TKAE) mouse lymphoma cells. 20 The role of the oxidative stress in PD has been debated and reviewed. 22 Data suggested that the oxidative damage by active radical species might contribute to the cascade of events leading to degeneration of DAergic neurons.…”

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“…These mimetics also act as supportive molecules for drugs. They protect the drug from fast metabolism and also prevent side effects 83 .…”

Solid-Phase Synthesis and In Vitro Cytotoxicity of New Peptide Functionalized Cyclencarboxymethylen and L-DOPA Hybrids

“…On the other hand, L-DOPA (3,4-dihydroxyphanylalanine) derivatives play a crucial role in the therapy of Parkinson disease (PD) as they increase the BBB penetration capacity of DOPA, which is well known medicine in the treatment of PD since 1960s. The DOPA peptidomimetics with amino acid cross-linked via oxygen atom were prepared and their antioxidant activities were studied [6].…”